The majority of “controlled-release” drug delivery systems known in the prior art (e.g., U.S. Pat. No. 4,145,410 to Sears which describes drug release from capsules which are enzymatically labile) are incapable of releasing drugs at intervals and concentrations which are in direct proportion to the amount of a molecular indicator (e.g., a metabolite) present in the human body. The delivery or release of drug in these prior art systems is thus not literally “controlled,” but simply a slow release which is independent of external or internal factors.
The treatment of diabetes mellitus with injectable insulin is a well-known and studied example where uncontrolled, slow release of insulin is undesirable. In fact, it is apparent that the simple replacement of the hormone is not sufficient to prevent the pathological sequelae associated with this disease. The development of these sequelae is believed to reflect an inability to provide exogenous insulin proportional to varying blood glucose concentrations experienced by the patient. To solve this problem several biological and bioengineering approaches to develop a more physiological insulin delivery system have been suggested.
U.S. Pat. No. 4,348,387 to Brownlee et al. discloses a feedback controlled insulin delivery system wherein glucose-insulin conjugates are displaced by free glucose from binding sites on a glucose-binding molecule. The conjugated insulin retains its biological activity once released. In practical applications, however, the system is soluble and must be enclosed within a membrane that is permeable to glucose and glucose-insulin but not to the glucose-binding molecule. Without the use of a membrane or other external device to maintain a high local concentration of the glucose-binding molecule, the system dissociates at infinite dilution and releases the conjugate in a non-glucose dependent manner. Such a system that is not self-contained and requires the use of membranes is limited to use in extracorporeal or implantable devices and is not directly applicable to repeated administration, e.g., by injection. Furthermore, the system works well when confronted with short pulses of glucose such that the total amount of glucose introduced into the system is much less than the total amount of glucose-insulin bound to the glucose binding sites on the binding molecule. However, in the physiological milieu, molar glucose concentrations are approximately one million times higher than the concentration of insulin required to achieve a physiological effect. The net result is that when confronted with a critical glucose concentration in vivo, there is always enough glucose around to effectively displace and release all of the glucose-insulin from the system. Such a system is, therefore, incapable of responding to repeated glucose challenges in vivo, which is ultimately required for a closed-loop delivery system.
U.S. Pat. Nos. 5,830,506, 5,902,603, and 6,410,053 to Taylor et al. have attempted to address the lack of response to repeated glucose challenges. Instead of enclosing a soluble competitive binding system within a membrane, they have developed insoluble membranes based on competitive binding that control the rate of insulin release from a reservoir. As with the Brownlee system, Taylor's system is designed to be used in extracorporeal or implantable devices. The insoluble membrane is in the form of a gel that is formed by physically crosslinking water-soluble, glycosylated polymers with the tetravalent glucose-binding molecule concanavalin A (Con A). Free glucose enters the gel where it competes with the glycosylated polymer for Con A and disrupts the crosslinks, causing a gel-to-sol transition. Insulin that is physically trapped within the insoluble gel is thereby released. The gel is sandwiched between two porous support membranes to minimize leakage of the glycosylated polymer and Con A.
Taylor's system has two advantages over Brownlee's: (1) the device is reversible and therefore capable of responding to repeated glucose challenges and (2) the insulin does not require chemical modification. However, the use of support membranes ultimately leads to a complex system with slow diffusion rates. Consequently, excessively high glucose concentrations (>400 mg/dl) are required to significantly increase insulin diffusion. Furthermore, once glucose is removed from the system, the decrease in insulin release rate lags behind by several hours. The Taylor system is also severely limited because insulin release is not directly coupled to glucose concentration. Rather, insulin release is governed by diffusion through the glucose-responsive gel.
Zion et al. (U.S. Patent Application Publication No. 2004-0202719 and “Glucose-responsive materials for self-regulated insulin delivery”, Thesis, Massachusetts Institute of Technology, Dept. of Chemical Engineering, 2004) address the lack of response to repeated glucose challenges in a different manner than Taylor. In certain embodiments of their system, they combine a multivalent glucose-binding molecule with a glycosylated polymer-insulin conjugate. The glycosylated polymer contains multiple saccharide binding groups and forms insoluble hydrogels or particles in the presence of the glucose-binding molecule. In the Brownlee system, the glucose-insulin conjugate was not polymeric and only contained one saccharide binding group per insulin molecule, which was not sufficient to form a cross-linked, insoluble system. In the Taylor system, the insulin is physically immobilized within the gel instead of being associated with a glycosylated polymer. Zion et al. also describe uses of their system for the controlled delivery of drugs other than insulin. These systems are responsive to the same or a different molecular indicator that is present within the body.
Because the Zion system is insoluble, it is self-contained and does not require the use of membranes to function, making it suitable for repeated dosing, e.g., through injection. Zion et al. have also demonstrated that the rate of dissolution in their system, and therefore the rate of polymer-drug release, is proportional to the local concentration of the indicator molecule. Finally, because the material dissolves from the outside inward rather than volumetrically, the material is capable of responding to repeated challenges, unlike the Brownlee system.
The Zion system is also superior to Taylor's because the drug is covalently linked to the polymer rather than physically immobilized in the system. As a result, precise control can be obtained over the dose and rate of delivery even for very small changes in concentration of the indicator molecule within the physiological range. For example, where Taylor et al. demonstrate a two- to four-fold increase in insulin release rate from 0 to 1,000 mg/dl glucose, Zion et al. have demonstrated a 50 fold increase in insulin release rate from just 50 to 400 mg/dl glucose.
Whether used to deliver insulin or other drugs, the Zion system suffers from one disadvantage. Indeed, the polymer-drug conjugate that is released has a higher molecular weight (MW) than the unmodified insulin of Taylor or the glucose-insulin conjugate of Brownlee. The conjugate is therefore absorbed into the systemic circulation much more slowly. In addition, once in the circulation, the intrinsic bioactivity of the polymer-drug is diminished and the rate of elimination is slower. Therefore, there is a need in the art for a stimuli-responsive drug delivery system constructed from a crosslinking molecule and a polymer-drug in which the polymer-drug acts as rapidly and to the same extent as the unmodified drug. Advantageously, this new polymer-drug could itself also be used as a delivery device, i.e., without being included within a stimuli-responsive drug delivery system.